The activity of the Src protein tyrosine kinase is elevated in over half of the human breast and colon cancers that have been examined, as well as in a variety of other tumors. Multiple data suggest that activated Src is an important partner or effector of other mutagenic events, particularly in tumor progression, metastasis and the suppression of apoptosis. However,. the mechanism of its activation is, in most cases, unknown. A likely candidate is protein tyrosine phosphatase (PTP) o_, which has been shown to directly dephosphorylate and activate Src. Our recent studies have shown that PTP_ plays a critical role in activating Src family members during mitosis. We will investigate if, together with Src, subversion of PTPE function contributes to neoplasia. We have found that PTP_ activates Src using a special targeting mechanism, and that increased PTPc_ activity and Src-specific targeting combine to enable PTPe_ cell cycle-specific activation of Src family members. We will elucidate the biochemical mechanism of this process and see if it, or a related process, stimulates Src in other physiological situations involving the control of cell growth, differentiation, and survival. With this understanding, we can develop and use more precise and sensitive assays to investigate the involvement of PTP_ with Src in cell proliferation and human cancer. In particular, we will pursue preliminary evidence suggesting that PTP_ suppresses the death of cancer cells. This knowledge will be useful for molecular diagnosis and prognosis, and can also help to identify specific new pharmacological targets within PTPe_, Src, and related proteins.